Franny Jongbloed

214 CHAPTER 8 inflammatory response 15 . The incidence of perioperative and postoperative complications in the kidney donors did not differ between groups either, which shows that concerns regarding a compromised immune response and wound healing following DR in a surgical setting are unwarranted and which underscores the safety of a CCPR diet 15 . The beneficial protective effects of the CCRP diet on the kidney were shown by significantly improved renal function: creatinine clearance and glomerular filtration rate in the first postoperative days until hospital discharge of the donors, as well as the significant decrease of serum urea concentrations both preoperatively and postoperatively. The improved postoperative kidney function in donors due to the CCPR diet in a setting of only marginal decrease in creatinine clearance due to kidney removal itself 18 , further underscores the powerful effects of the CCPR diet. Subgroup analyses showed a common improved renal outcome in both male and female donors, albeit this improvement seemed to occur earlier after surgery in females. The ameliorated outcome in the kidney donors is further strengthened by the significantly, clinically highly relevant improvement of creatinine clearance in the kidney transplant recipients from CCPR donors. Interestingly, male recipients appeared to show better serum creatinine clearance compared to female recipients. To determine whether females have a different susceptibility to IRI or response to DR, these results need to be validated in larger cohorts. Transplant recipients of CCPR donors showed a trend towards higher Tacrolimus pre-dose concentrations which suggests CCPR alters the metabolism of Tac. Despite higher exposure to Tac, which is correlated with increased nephrotoxicity 19 , the creatinine clearance was superior in the CCPR recipients. Together with the significantly lower incidence of acute rejection and SGF, these data indicate that short-term CCPR induces increased stress resistance in humans resulting in protecting the transplanted kidney from ischemic damage and from acute rejection. Two recipients in the control group developed uncontrollable acute rejection which necessitated transplant nephrectomy 20 . However, these patients received belatacept rather than Tac-based immunosuppression. Although non-nephrotoxic, belatacept is a less potent immunosuppressant than Tac, we feel that these two severe cases of rejection are explained by the type of immunosuppressive therapy 21 . Excluding both patients from the statistical analysis did not impact the creatinine clearance and eGFR results in the recipients (data not shown). Transcriptome analysis in kidney tissue obtained during surgery revealed changes in cell cycle and stress resistance pathways due to the CCPR diet. In particular, the suggested inhibition of cell cycle G2M phase regulation and upregulation of NRF2-mediated stress response and eIF2 signaling revealed a strong overlap with our preclinical data in kidneys of mice subjected to protein-free, calorie-restricted or fasting diets 12,14,22 . Activation of